Field of the Invention
The present invention relates to modulation of angiogenesis, such as the inhibition of angiogenesis in cancer and other diseases in which there is excessive angiogenesis and the promotion of angiogenesis in diseases or conditions in which there is insufficient angiogenesis.
Description of the Related Art
Angiogenesis is an intricate progression which takes part in normal states such as embryo development and menstrual cycle but is also related to several pathologies including wound healing, cancer, macular degeneration and ischemia (Risau 1997; Maas et al., 2001; Tonnesen et al., 2000; Kerbel 2008; and Napoleone et al., 2005). More recently, accumulating data links angiogenesis with a broader range of pathologies including inflammatory and neurodegenerative diseases (Beat et al., 2006; Creamer et al., 2003; and Hosoi et al., 2010). Anti-angiogenesis agents such as bevacizumab, sunitinib and sorafenib have already been proven to be beneficial in cancer therapy, especially in combination with chemotherapy (Hurwitz et al., 2004; Sunitinib et al., 2010; and Ghassan et al., 2010), establishing anti-angiogenesis therapy as one of the fourth modality of cancer treatment together with surgery, chemotherapy and radiotherapy.
Many factors that regulate angiogenesis have been identified. It is well established that among them vascular endothelial growth factor (VEGF) and angiopoeitin 1 and 2 (Ang1/2) are key players in modulating the formation of new blood vessels and numerous reports describe the profound effect when their natural balance is disturbed. Ang1 and Ang2 are ligands of Tie2 tyrosine kinase receptor. While Ang1 functions as Tie2 agonist the role of Ang2 is less understood and is generally referred to as a context dependent agonist/antagonist. Signals mediated by Tie2 promote fundamental processes in angiogenesis particularly by manipulating endothelial cells (EC) activity. Notably, Tie2 was demonstrated to induce EC migration, adhesion to extra cellular matrix (ECM) proteins and tube formation. Furthermore, binding of Ang2 or Ang1 to Tie2 modulates vessel stability by either promoting pericytes dissociation from pre-existing quiescent vessels or recruiting pericytes to support nascent vessels respectively (Dvorak, 2005; Huang et al., 2010; and Matijs et al., 2009).
Treatment with filamentous bacteriophage displaying a melanoma tumor-specific peptide (amino acid residues RRKRMTILKSRM (SEQID NO:2) or TRTKLPRLHLQS (SEQ ID NO:3)) or an HLA-A2 specific Fab fragment resulted in regression of established melanoma tumors in mice (Eriksson et al., 2007 and 2009).
Vascular endothelial growth factor (VEGF) displayed on filamentous bacteriophage was combined with a type I collagen scaffold and, in the presence of human micro-vascular endothelial cells (hMVECs), was shown to promote angiogenesis of hMVECs on the scaffold of phage-VEGF bound collagen (Yoon et al., 2012)
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